8-11708563-A-G

Variant names:

• chr8-11708563-A-G
• rs899093640
• NM_001308093.3:c.251A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001308093.3(GATA4):​c.251A>G​(p.Gln84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000243 in 1,232,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: GATA4 NM_001308093.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.86

Genes affected

GATA4 (HGNC:4173): (GATA binding protein 4) This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA4	NM_001308093.3	c.251A>G	p.Gln84Arg	missense_variant	Exon 2 of 7	ENST00000532059.6	NP_001295022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA4	ENST00000532059.6	c.251A>G	p.Gln84Arg	missense_variant	Exon 2 of 7	1	NM_001308093.3	ENSP00000435712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000243 AC: 3 AN: 1232410 Hom.: 0 Cov.: 31 AF XY: 0.00000166 AC XY: 1 AN XY: 601098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000592

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrioventricular septal defect 4 Uncertain:1

Oct 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GATA4 protein function. ClinVar contains an entry for this variant (Variation ID: 577466). This variant has not been reported in the literature in individuals affected with GATA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 84 of the GATA4 protein (p.Gln84Arg). -

Cardiovascular phenotype Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q84R variant (also known as c.251A>G), located in coding exon 1 of the GATA4 gene, results from an A to G substitution at nucleotide position 251. The glutamine at codon 84 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.70	D;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.8	L;.;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.35	N;N;N;.
REVEL	Uncertain	0.61
Sift	Benign	0.11	T;D;T;.
Sift4G	Benign	0.64	T;T;T;T
Polyphen		0.61	P;.;.;.
Vest4		0.38
MutPred		0.54		Gain of methylation at Q84 (P = 0.0332);Gain of methylation at Q84 (P = 0.0332);Gain of methylation at Q84 (P = 0.0332);.;
MVP		0.89
MPC		0.091
ClinPred		0.48	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs899093640; hg19: chr8-11566072;